Kristen Kitzler Group 6 April 20, 2010 Cushing’s disease Introduction: Cushing disease is caused by an excess of Adrenocorticotropic hormone (ACTH) produced by neuroendocrine tumors, which subsequently result in chronic glucorticoid excess. Hormonal disorders are caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol (1). Sometimes called hypercortisolism, Cushing’s disease is relatively rare and most commonly affects adults aged 20 to 50. People who are obese and have type 2 diabetes, along with poorly controlled blood glucose and high blood pressure, have an increased risk of developing this disorder. Signs and symptoms of Cushing’s syndrome vary, but most people with the disorder have upper body obesity, a rounded face, increased fat around the neck, and relatively slender arms and legs (2). Objectives: Based on the actions of retinoic acid on AP-1 and Nur77 and on their involvement in ACTH biosynthesis, the effects of retinoic acid on ACTH-secreting tumor cells that cause Cushing syndrome were examined (1). Sodium: Renal sodium retention may contribute to hypertension in Cushing syndrome, with sodium balance being restored at the expense of elevated blood pressure (2). Materials & Methods: Retinoic Acid: ACTH-secreting experimental tumors were formed by injecting AtT-20 cells into a subdermal pouch in BALB/c AnN Crl-nu BR nude mice. To evaluate retinoic acid effects on tumor formation, cells that had been treated with retinoic acid for 3 hours in vitro were trypsinized, checked for vitality, and injected into nude mice. Tumor formation was monitored after 2 and 5 weeks. In a separate set of experiments, mice with 2-week-old tumors were treated with intraperitoneal injections of 10 mg/kg retinoic acid dissolved in peanut oil. The treatment was repeated every 4 days for 3 weeks (1). Sodium: Cohorts of male mice were maintained on either a standard rodent diet or a low-sodium diet with free access to water (2). Results: Retinoic Acid: Retinoic Acid inhibits cell proliferation and after prolonged treatment increased capase -3 activities and induced cell death in ACTH secreting cells. Researchers concluded that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome (1). Sodium: ACTH treated mice had a significantly higher hematocrit level than saline control, which was attributed to hemoconcentration depletion of plasma volume was confirmed. ACTH treated mice were hypokalemic and hypernatremic which let to elevated sodium levels in the blood (2). Summary: Through research, it is seen that both Retinoic Acid and Sodium have lasting effects on patients with Cushing’s disease. Retinoic Acid will help inhibit ACTH secreting cells from growing. This in turn, is a positive effect and will allow patients to maintain their disease. Increased sodium can increase the amount of ACTH cells in the body and will help to increase blood pressure that can lead to hypertension. A low sodium diet is need in patients with Cushing’s disease to maintain their blood pressure and prevent hypertension (1,2). Discussion: Retinoic acid inhibits the AP-1 and Nur77/Nurr1 transcriptional activities in ACTH-secreting cells. These results are in line with previous studies on other cells that demonstrate that retinoic acid can inhibit AP-1–dependent genes and also represses Nur77 transactivation activity. We further demonstrate that retinoic acid inhibits POMC transcription, which is controlled by AP-1, Nur77, and Nurr1 (1). Sodium: ACTH infusion induces a robust pressor response in humans and experimental animals, associated with reduced sodium excretion. There was a highly significant correlation between the amiloride-sensitive sodium reabsorption and blood pressure. References: 1. Paez-Pereda M, Kovlovsky D, Hopfner U, Theodoropoulou M, Pagotto U, Uhl E, Losa M, Stalla J, Grubler Y, Missale C, Arzt E, Stalla G. Retinoic acid prevents experimental Cushing syndrome by the Journal of Clinical Investigation. 2001; 108; 1123-1131. 2. Bailey MA, Mullins JJ, Kenyon CJ. Hypertension by American Heart Association. 2009; 54; 890-896.
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